Peripheral arterial occlusive disease is a disease in which the artery is constricted or occluded due to arteriosclerosis and thrombus formation, the periphery, particularly the lower limb, falls into an ischemic state, and exhibits symptoms such as cryaesthesia, intermittent claudication, pain, and ulcer or necrosis of lower limb. Improvement of the blood flow to the ischemic part is important for improving the lower limb symptoms, and treatments aiming at resuming blood circulation by drugs or physical methods are performed. Drugs having vasodilating action and platelet aggregation inhibiting action are used for drug therapy.
Peripheral vascular disease also manifests as atherosclerotic stenosis of the renal artery and can lead to renal ischemia and kidney dysfunction. Chronic diabetes can also lead to atherosclerosis and vascular complications involving large vessel, arteriole and capillary. Diabetic patients are at high risk of developing foot ulcer due to long-term complications of, for example, neuropathy and ischemia.
Spinal canal stenosis is a disease in which the spinal canal is narrowed due to hypertrophy degeneration of the spine and the ligamentum flavum that constitute the spinal canal and protrusion of the intervertebral disc, and neural tissues such as the nerve root and cauda equina are compressed and various symptoms are exhibited. Spinal canal stenosis is classified into extensive spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis and the like according to the narrow portion of the spinal canal. The symptoms thereof include lumbago, pain in the upper limb or lower limb, numbness and the like due to nerve compression. In particular, when the cauda equina is injured, lumbago, lower limb pain, numbness, weakness become severe during walking, and this symptom is called intermittent claudication.
Natural prostaglandins (hereinafter prostaglandin is to be indicated as PG) are a group of bicactive substances synthesized in vivo, and regulate cellular functions of each tissue of the body as a topical hormone having various physiological activities. In particular, PGE1s, which are one kind of natural PGs, have, for example, a vasodilating action, an angiogenesis action, a platelet aggregation suppressive action, and an epithelial regeneration promoting action. They are used as an antiplatelet agent, an agent for improving peripheral blood flow disorders and the like in the drug therapy of the above-mentioned diseases. While PGEs may be applicable to other indications, natural PGEs are extremely unstable chemically and metabolically. Thus, the development of PGE derivatives which are more stable and effective, and cause fewer side effects has been extensively studied.
A PG derivative having a double bond at the 2-position of PG and a production method thereof are reported in the following patent documents 1-5 and non-patent documents 1-2. In addition, a PG derivative having an alkynyl group in the ω-chain of PG and a production method thereof are reported in the following patent documents 6-7.